PRC2
EZH2型
化学
体内
组蛋白甲基转移酶
癌症研究
甲基转移酶
共价键
组蛋白
药理学
生物化学
生物
甲基化
遗传学
有机化学
基因
作者
Qiangsheng Zhang,Xinyi Chen,Jiaying Cao,Wan Seok Yang,Guoquan Wan,Qiang Feng,Shao-Lai Zhou,Hongling Yang,Ningyu Wang,Zhihao Liu,Hongtao Xiao,Yiping Zhu,Luoting Yu
标识
DOI:10.1021/acs.jmedchem.2c01370
摘要
Enhancer of zeste homologue 2 (EZH2) is the enzymatic catalytic subunit of polycomb repressive complex 2 (PRC2), which plays an important role in post-translational modifications of histones. In this study, we designed and synthesized a new series EZH2 covalent inhibitors that have rarely been reported. Biochemical studies and mass spectrometry provide information that SKLB-03220 could covalently bind to the S-adenosylmethionine (SAM) pocket of EZH2. Besides, SKLB-03220 was highly potent for EZH2MUT, while exhibiting weak activities against other tested histone methyltransferases (HMTs) and kinases. Moreover, SKLB-03220 displayed noteworthy potency against ovarian cancer cell lines and continuously abolished H3K27me3 after washing out. Furthermore, oral administration of SKLB-03220 significantly inhibited tumor growth in PA-1 xenograft model without obvious adverse effects. Taken together, SKLB-03220 is a potent, selective EZH2 covalent inhibitor with noteworthy anticancer efficacy both in vitro and in vivo.
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